Preliminary analysis of genomic abnormalities in canine meningiomas.

Cytogenetic detection of unbalanced genomic aberrations in tumours is a strategy for the identification of tumour suppressor genes and oncogenes. When considered in concert with clinical data, the approach also represents a means of identifying markers of prognosis. In a preliminary investigation of the molecular basis of canine meningioma tumorigenesis, we profiled three tumours by comparative genomic hybridization. Distinct patterns of sub-chromosomal deletions were identified suggesting alternative mechanisms of tumour initiation. The deleted chromosomal segments encompass two regions (10q23.1 and 17q22-q23) that are syntenic to the chromosomes (22 and 1p) most often deleted in human meningiomas. A number of genes associated with DNA repair, cell cycle progression and apoptosis are located on both the deleted canine chromosomal segments and the syntenic regions deleted in human meningiomas. This study represents the first report of chromosomal copy number abnormalities in non-cultured canine brain tumour tissue.

Extensive coloured identification of dog chromosomes to support karyotype studies: the colour code.

The identification of individual dog chromosomes is problematic because the 38 pairs of autosomes are small and acrocentric. Here we describe the design and application of a FISH tool that enables definitive identification of each dog autosome in a normal karyotype, without relying on subjective interpretation of DAPI banding patterns. From a high-resolution physical map of the canine genome, we have chosen a panel of 80 canine chromosome-specific BAC clones. DNA from each clone is labeled with one of five different fluorochrome-conjugated nucleotides. By selecting one to three spatially separated BACs per chromosome, and labelling them with a distinctive combination of colours, each autosome can be identified objectively and orientated accurately, irrespective of the quality of DAPI chromosome banding. This tool, or part of it, can be used for any purpose where accurate identification of canine autosomes in a normal karyotype is essential. In this study, we demonstrate use of the 'colour code' for chromosome identification following CGH analysis of unbalanced genomic aberrations in a canine brain tumour. Our method is an improvement of an earlier procedure, featuring chromosome-specific BACs and sequential FISH hybridisations, as it enables simultaneous identification of all chromosomes in a single hybridisation.

High-resolution analysis of chromosome rearrangements on 8p in breast, colon and pancreatic cancer reveals a complex pattern of loss, gain and translocation.

The short arm of chromosome 8, 8p, is often rearranged in carcinomas, typically showing distal loss by unbalanced translocation. We analysed 8p rearrangements in 48 breast, pancreatic and colon cancer cell lines by fluorescence in situ hybridization (FISH) and array comparative genomic hybridization, with a tiling path of 0.2 Mb resolution over 8p12 and 1 Mb resolution over chromosome 8. Selected breast lines (MDA-MB-134, MDA-MB-175, MDA-MB-361, T-47D and ZR-75-1) were analysed further. Most cell lines showed loss of 8p distal to a break that was between 31 Mb (5' to NRG1) and the centromere, but the translocations were accompanied by variable amplifications, deletions and inversions proximal to this break. The 8p12 translocation in T-47D was flanked by an inversion of 4 Mb, with a 100 kb deletion at the proximal end. The dicentric t(8;11) in ZR-75-1 carries multiple rearrangements including interstitial deletions, a triplicated translocation junction between NRG1 and a fragment of 11q (unconnected to CCND1), and two separate amplifications, of FGFR1 and CCND1 . We conclude that if there is a tumour suppressor gene on 8p it may be near 31 Mb, for example WRN; but the complexity of 8p rearrangements suggests that they target various genes proximal to 31 Mb including NRG1 and the amplicon centred around ZNF703/FLJ14299.

Molecular cytogenetic analysis of breast cancer cell lines.

The extensive chromosome rearrangements of breast carcinomas must contribute to tumour development, but have been largely intractable to classical cytogenetic banding. We report here the analysis by 24-colour karyotyping and comparative genomic hybridization (CGH) of 19 breast carcinoma cell lines and one normal breast epithelial cell line, which provide model examples of karyotype patterns and translocations present in breast carcinomas. The CGH was compared with CGH of 106 primary breast cancers. The lines varied from perfectly diploid to highly aneuploid. Translocations were very varied and over 98% were unbalanced. The most frequent in the carcinomas were 8;11 in five lines; and 8;17, 1;4 and 1;10 in four lines. The most frequently involved chromosome was 8. Several lines showed complex multiply-translocated chromosomes. The very aneuploid karyotypes appeared to fall into two groups that evolved by different routes: one that steadily lost chromosomes and at one point doubled their entire karyotype; and another that steadily gained chromosomes, together with abnormalities. All karyotypes fell within the range seen in fresh material and CGH confirmed that the lines were broadly representative of fresh tumours. The karyotypes provide a resource for the cataloguing and analysis of translocations in these tumours, accessible at http://www.path.cam.ac.uk/ approximately pawefish.

Chromosome translocations in breast cancer with breakpoints at 8p12.

Unbalanced chromosome translocations with breakpoints around 8p12, resulting in loss of distal 8p, are common in carcinomas. We have mapped the 8p12 breakpoints in three breast cancer cell lines, T-47D, MDA-MB-361, and ZR-75-1, using YACs and PACs between D8S540 and D8S255 by fluorescence in situ hybridization. All three lines had a breakpoint close to D8S505, proximal to HGL. Each breakpoint was distinct, but all were within 0.5 to 1.5 Mb of each other. The T-47D cell line had a straightforward translocation, but in MDA-MB-361 and ZR-75-1 the translocations were accompanied by local rearrangements of surprising complexity. Small regions of 8p from close to the breakpoint were duplicated or amplified as inserts in the attached chromosome fragment. ZR-75-1 also had retained a separate fragment of about 1 Mb, from the region 1 to 3 Mb telomeric to the common breakpoint, that included HGL. This line also had an interstitial deletion several megabases more centromeric. The data suggest that breakpoints on 8p12 are clustered in a small region and show that translocations breaking there may be accompanied by additional rearrangements.

Redefining body composition: nutrients hormones, and genes in meat production.

Growth rate and body composition of livestock can be optimized to meet consumer needs for a leaner product and to improve the efficiency of meat-animal production. Optimization strategies have traditionally focused on genetic selection and cost-effective ration formulation to achieve the genetic potential. Advances in understanding the mechanisms of growth and its control have led to additional opportunities for its manipulation. These include nutritional manipulation,the use of growth promotants, and, more recently, the ability to change the genetic potential through genetic engineering. Selection of appropriate candidate genes for manipulation depends on understanding the mechanisms underlying differentiation and growth of embryonic muscle cells. Recent advances in genetic engineering techniques, including gene therapy and germline transgenesis, will likely hasten the genetic progress toward a leaner carcass in domestic livestock. Such strategies may prove to be more beneficial then the controlled enhancement of somatotropin expression.

Suppression of tubulin tyrosine ligase during tumor growth.

The C terminus of the tubulin alpha-subunit of most eukaryotic cells undergoes a cycle of tyrosination and detyrosination using two specific enzymes, a tubulin tyrosine ligase (TTL) and a tubulin carboxypeptidase. Although this enzyme cycle is conserved in evolution and exhibits rapid turnover, the meaning of this modification has remained elusive. We have isolated several NIH-3T3 derived clonal cell lines that lack TTL (TTL-). TTL- cells contain a unique tubulin isotype (delta2-tubulin) that can be detected with specific antibodies. When injected into nude mice, both TTL- cells and TTL- cells stably transfected with TTL cDNA form sarcomas. But in tumors formed from TTL rescued cells, TTL is systematically lost during tumor growth. A strong selection process has thus acted during tumor growth to suppress TTL activity. In accord with this result, we find suppression of TTL activity in the majority of human tumors assayed with delta2-tubulin antibody. We conclude there is a widespread loss of TTL activity during tumor growth in situ, suggesting that TTL activity may play a role in tumor cell regulation.

[Right coronary ostial stenosis in homozygotic hypercholesterolemia. Coronarographic and echocardiographic diagnosis]. / Sténoses ostiales coronaires droites dans l'hypercholestérolémie homozygote. Diagnostic coronarographique et échocardiographique.

Ostial stenosis of the right coronary artery was discovered in 2 patients with homozygous familial hypercholesterolaemia. The lesion was confirmed in one case at post-mortem examination and in the other case by cross-sectional echocardiography. In both patients the stenosis could not be visualized at coronary arteriography when the right coronary vessel was selectively injected, but the lack of reflux of the contrast medium into the aortic sinus proved very useful for the diagnosis. To recognize this sign is important since the other criteria of ostial stenosis are not always present, notably in essential hypercholesterolaemia where post-stenosis dilatation is absent due to diffuse parietal lesions of the arteries. In addition, ostial stenoses are associated with a characteristic stenosis localized to the proximal aorta above the coronary ostia. Owing to the dangers of overlooking ostial stenoses, echocardiography and aortography should be performed before coronary arteriography, and the lack of reflux of the contrast medium should be acknowledged as a diagnostic sign.

[Treatment of frostbites. Analysis of results in twenty patients with buflomedil chlorhydrate (author's transl)]. / Le traitement des gelures de montagne. Analyse des résultats obtenus sur vingt gelés par le chlorhydrate de buflomedil.

Twenty cases of mountain frostbites of various degrees are presented, showing that buflomedil hydrochloride allows an improvement of the usual treatment of frostbites. Two protocols were used: 1) in 8 patients, after the usual treatment (bath at 38 degrees C, dextran perfusion, heparintherapy, antibiotherapy), buflomedil hydrochlorhydrate was administered by perfusion of 8 vials/day, during 10 days; 2) in 12 patients, buflomedil was injected directly by intravenous route on their arrival in the Emergency room. When the injection is given early, a potentiation of the effects of the warm bath is observed, and in two cases, this therapy has perhaps allowed to avoid the amputation.

[Current indications of coronary arteriography in coronary artery disease (with the exception of acute myocardial infarction) (author's transl)]. / Indications actuelles de la coronarographie dans la maladis coronarienne (a l'exclusion de l'infarctus myocardique aigu).

The indications of coronary arteriography have multiplied in recent years. Therapeutic indications have followed knowledge of the good results of revascularisation surgery. Initially limited to severe stable angina improved little or not at all by major anti-angina agents, they have been extended, in the view of many, to include various types of unstable angina where, in addition to the symptomatic improvement obtained, an attempt is made to decrease the incidence of myocardial infarction and of long term mortality. Indications relative to determination of the extent of disease may be preventive: the fear of severe coronary lesions on the basis of effort test results, the fear of a second infarction immediately following a primary lesion, or as a virtually routine examination in young individuals in order to better assess the degree of disease and to guide treatment. Diagnostic indication should be rare.

[Auriculo-ventricular perforation in bacterial endocarditis. Surgical treatment]. / Perforations auriculo-ventriculaires au cours d'une endocardite bactérienne. Guérison chirurgicale

The authors report a case of bacterial endocarditis during which the precise nature of the heart lesions were only discovered at operation. There left ventricle and right atrium. The characteristics of the systolic murmur and the findings on phonocardiography together with left ventricular angiography had suggested mitral incompetence. There were no conduction disorders in this patient which might have helped in preoperative diagnosis. In connection with this case, the authors recall the characteristics of aneuryms of the membranous septum and congenital or acquired communications between the left venticle and the right atrium.